title: Immunology taught by human genetics.
abstract: Human genetic studies are rarely conducted for immunological purposes. Instead, they are typically driven by medical and evolutionary goals, such as understanding the predisposition or resistance to infectious or inflammatory diseases, the pathogenesis of such diseases, and human evolution in the context of the long-standing relationships between humans and their commensal and environmental microbes. However, the dissection of these experiments of Nature has also led to major immunological advances. In this review, we draw on some of the immunological lessons learned in the three branches of human molecular genetics most relevant to immunology: clinical genetics, epidemiological genetics, and evolutionary genetics. We argue that human genetics has become a new frontier not only for timely studies of specific features of human immunity, but also for defining general principles of immunity. These studies teach us about immunity as it occurs under "natural" conditions, through the transition from the almost complete wilderness that existed worldwide until about a century ago to the current unevenly distributed medically shaped environment. Hygiene, vaccines, antibiotics, and surgery have considerably decreased the burden of infection, but these interventions have been available only recently, so have yet to have a major impact on patterns of genomic diversity, making it possible to carry out unbiased evolutionary studies at the population level. Clinical genetic studies of childhood phenotypes have not been blurred by modern medicine either. Instead, medical advances have actually facilitated such studies, by making it possible for children with life-threatening infections to survive. In addition, the prevention and treatment of infectious diseases have increased life expectancy at birth from ∼20 yr to ∼80 yr, providing unique opportunities to study the genetic basis of immunological phenomena against which there is no natural counterselection, such as reactivation and secondary infectious diseases and breakdown of self-tolerance manifesting as autoimmunity, in populations of adult and aging patients. Recently developed deep sequencing and stem cell technologies are of unprecedented power, and their application to human genetics is opening up exciting and timely possibilities for young immunologists seeking uncharted waters to explore.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980, Necker Hospital for Sick Children, Paris 75015, France Paris Descartes University, Imagine Institute, Necker Hospital, Paris 75015, France casanova@rockefeller.edu.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980, Necker Hospital for Sick Children, Paris 75015, France Paris Descartes University, Imagine Institute, Necker Hospital, Paris 75015, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Unit of Human Evolutionary Genetics, Pasteur Institute, Paris 75015, France CNRS URA 3012, Paris 75015, France.
authors.forename: Lluis
authors.initials: L
authors.lastname: Quintana-Murci
mesh_terms: D000483:Alleles; D005075:Biological Evolution; D003141:Communicable Diseases / Q000235:genetics; D004247:DNA / Q000737:chemistry; D005826:Genetics, Medical / Q000379:methods*; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D007158:Immunologic Techniques; D055552:Infectious Disease Medicine / Q000379:methods; D017720:Molecular Epidemiology; D009154:Mutation; D010641:Phenotype; D012107:Research Design; D050794:STAT1 Transcription Factor / Q000235:genetics; D013234:Stem Cells / Q000166:cytology
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D004247:DNA